Cyclic amine phenyl beta-3 adrenergic receptor agonists

Details Cyclic amine phenyl beta-3 adrenergic receptor agonists Cyclic amine phenyl beta-3 adrenergic receptor agonists

2001-07-12

2003-02-25

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S192000, C546S022000

Reexamination Certificate

active

06525202

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to cyclic amine phenyl &bgr;
3
adrenergic receptor agonists useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
The subdivision of &bgr; adrenergic receptors (&bgr;-AR) into &bgr;
1
- and &bgr;
2
-AR has led to the development of &bgr;
1
- and &bgr;
2
-antagonists and/or agonists which have been useful for the treatment of cardiovascular disease and asthma. The recent discovery of “atypical” receptors, later called &bgr;
3
-AR, has led to the development of &bgr;
3
-AR agnoists which may be potentially useful as antiobesity and antidiabetic agents. For recent reviews on &bgr;
3
-AR agnoists , see: 1. A. D. Strosberg,
Annu. Rev. Pharmacol. Toxicol.
1997, 37, 421; 2. A. E. Weber,
Ann. Rep. Med. Chem.
1998, 33, 193; 3. C. P. Kordik and A. B. Reitz,
J. Med. Chem.
1999, 42, 181; 4. C. Weyer, J. F. Gautier and E. Danforth,
Diabetes and Metabolism,
1999, 25, 11.
Compounds that are potent and selective &bgr;
3
agonists, may be potentially useful antiobesity agents. Low levels or lack of &bgr;
1
and &bgr;
2
-agonistic properties will minimize or eliminate the adverse side effects that are associated with &bgr;
1
and &bgr;
2
agonistic activities, i.e. increased heart rate, and muscle tremor, respectively. Early developments in the &bgr;
3
-agonist field are described in European patent 427480, U.S. Pat. Nos. 4,396,627, 4,478,849, 4,999,377, and 5,153,210. These early patents purport to claim compounds with greater selectivity for the &bgr;
3
-AR than for the &bgr;
1
- and &bgr;
2
-AR's. However, clinical trials in humans with such compounds have not been successful to date.
More recently, potent and selective human &bgr;
3
agonists have been described in several patents and published applications: WO 98/32753, WO 97/46556, WO 97/37646, WO 97/15549, WO 97/25311, WO 96/16938, WO 95/29159, European Patents 659737, 801060, 714883, 764640, 827746, and U.S. Pat. Nos. 5,561,142, 5,705,515, 5,436,257, and 5,578,620. These compounds were evaluated in Chinese hamster ovary (CHO) cells test procedures which predicts the effects that can be expected in humans. These assays utilize cloned human &bgr;3 receptors, expressed in CHO cells (see refs. Granneman et al.,
Mol Pharmacol.,
1992, 42, 964; Emorine et al.,
Science,
1989, 245, 1118; Liggett
Mol. Pharmacol.,
1992, 42, 634).
&bgr;
3
-Adrenergic agonists also are useful in controlling the frequent urge of urination. It has been known that relaxation of the bladder detrusor is under beta adrenergic control (Li J, Yasay G and Kau S. Beta-adrenoceptor subtypes in the detrusor of guinea-pig urinary bladder.
Pharmacology
1992; 44: 13-18). Recently, a number of laboratories have provided experimental evidence in a number of animal species including human (Yamazaki Y, Takeda H, Akahane M, Igawa Y, et al. Species differences in the distribution of the beta-adrenoceptor subtypes in bladder smooth muscle.
Br. J. Pharmacol.
1998; 124: 593-599) that activation of the &bgr;
3
receptor subtype by norepinephrine is responsible for relaxation of the urinary bladder. Urge urinary incontinence is characterized by abnormal spontaneous bladder contractions that can be unrelated to bladder urine volume. Urge urinary incontinence is often referred to hyperactive or unstable bladder. Several etiologies exist and fall into two major categories, myogenic and neurogenic. The myogenic bladder is usually associated with detrusor hypertrophy secondary to bladder outlet obstruction, or with chronic urinary tract infection. Neurogenic bladders are associated with an uninhibited micturition reflex. An upper motor neuron disease is usually the underlying cause. In either case, the disease is characterized by abnormal spontaneous contractions that result in an abnormal sense of urinary urgency and involuntary urine loss. At present, the most common therapy for hyperactive bladder includes the use of antimuscarinic agents to block the action of the excitatory neurotransmitter acetylcholine. While effective in neurogenic bladders, their utility in myogenic bladders is questionable. In addition, due to severe dry mouth side-effects associated with antimuscarinic therapy, the patient compliance with these agents is only approximately 30%.
In the bladder, &bgr;
3
adrenergic receptor agonists activate adenylyl cyclase and generate cAMP through the G-protein coupled &bgr;
3
receptor. The resulting phosphorylation of phospholamban/calcium ATPase enhances uptake of calcium into the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits bladder smooth muscle contractility.
It is suggested therefore, that activation of the &bgr;
3
adrenergic receptor in the urinary bladder will inhibit abnormal spontaneous bladder contractions and be useful for the treatment of bladder hyperactivity. Note, that unlike the antimuscarinics, &bgr;
3
adrenergic receptor agonists would be expected to be active against both neurogenic and myogenic etiologies.
Despite all these recent developments there is still no single therapy available for the treatment of type II diabetes (NIDDM), obesity, atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, frequent urination and related diseases. A potent and selective &bgr;
3
adrenergic receptor agonist is therefore highly desirable for the potential treatment of such disease states.
DESCRIPTION OF THE INVENTION
This invention provides compounds of Formula I having the structure
wherein
A is Ar or Het;
X is —OCH
2
—, —SCH
2
—, or a bond;
T
1
is (CH
2
)
m
;
T
2
is (CH
2
)
n
;
T is a bond, alkyl of 1-6 carbon atoms optionally substituted with R
11
, alkenyl of 2-7 carbon atoms optionally substituted with R
11
, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety, alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7 carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms;
R
1
, R
2
, and R
3
are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, dihydroxyphosphorylamino, —CO
2
-alkyl of 1-6 carbon atoms, or Ar optionally substituted with R
11
;
R
4
is hydrogen, alkyl of 1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, carboxy, acyl of 2-7 carbon atoms, ArCO-, alkoxycarbonyl of 2-7 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbon atoms,
R
5
is
Aa is (i) an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R
5
; or (ii) an alkyl ester of an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R
5
, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms;
Y and Z are each, independently, NR
7
, O, or S;
X
1
and X
2
are each, independently, CO or SO
2
;
a dotted line represents and optional double bond;
R
6
, R
7
, and R
8
are each, independently, hydrogen; alkyl of 1-6 carbon atoms optionally substituted by R
11
, R
12
, and R
13
; alkenyl of 2-7 carbon atoms op tionally substituted by R
11
, R
12
, and R
13
; alkynyl of 2-7 carbon

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